Alcohol
Metabolism: An Update

Drinking heavily puts people
at risk for many adverse health consequences, including alcoholism, liver damage,
and various cancers. But some people appear to be at greater risk than others
for developing these problems. Why do some people drink more than others? And
why do some people who drink develop problems, whereas others do not?

Research
shows that alcohol use and alcohol-related problems are influenced by individual
variations in alcohol metabolism, or the way in which alcohol is broken down and
eliminated by the body. Alcohol metabolism is controlled by genetic factors, such
as variations in the enzymes that break down alcohol; and environmental factors,
such as the amount of alcohol an individual consumes and his or her overall nutrition.
Differences in alcohol metabolism may put some people at greater risk for alcohol
problems, whereas others may be at least somewhat protected from alcohol’s
harmful effects.

This Alcohol Alert describes
the basic process involved in the breakdown of alcohol, including how toxic byproducts
of alcohol metabolism may lead to problems such as alcoholic liver disease, cancer,
and pancreatitis. This Alert also describes populations who may be at
particular risk for problems resulting from alcohol metabolism as well as people
who may be genetically “protected” from these adverse effects.

THE
CHEMICAL BREAKDOWN OF ALCOHOL

Alcohol is metabolized
by several processes or pathways. The most common of these pathways involves two
enzymes—alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). These
enzymes help break apart the alcohol molecule, making it possible to eliminate
it from the body. First, ADH metabolizes alcohol to acetaldehyde, a highly
toxic substance and known carcinogen (1). Then, in a second step, acetaldehyde
is further metabolized down to another, less active byproduct called acetate
(1), which then is broken down into water and carbon dioxide for easy elimination
(2).

Other
enzymes—

The enzymes cytochrome P450
2E1 (CYP2E1) and catalase also break down alcohol to acetaldehyde. However, CYP2E1
only is active after a person has consumed large amounts of alcohol, and catalase
metabolizes only a small fraction of alcohol in the body (1). Small amounts of
alcohol also are removed by interacting with fatty acids to form compounds called
fatty acid ethyl esters (FAEEs). These compounds have been shown to contribute
to damage to the liver and pancreas (3).

The Chemical Breakdown of Alcohol

The chemical name for alcohol is ethanol (CH3CH2OH).
The body processes and eliminates ethanol in separate steps. Chemicals called
enzymes help to break apart the ethanol molecule into other compounds (or metabolites),
which can be processed more easily by the body. Some of these intermediate metabolites
can have harmful effects on the body.

Most of the ethanol in
the body is broken down in the liver by an enzyme called alcohol dehydrogenase
(ADH), which transforms ethanol into a toxic compound called acetaldehyde (CH3CHO),
a known carcinogen. However, acetaldehyde is generally short-lived; it is quickly
broken down to a less toxic compound called acetate (CH3COO-)
by another enzyme called aldehyde dehydrogenase (ALDH). Acetate then is broken
down to carbon dioxide and water, mainly in tissues other than the liver.

Acetaldehyde:
a toxic byproduct—Much of the research on alcohol metabolism
has focused on an intermediate byproduct that occurs early in the breakdown process—acetaldehyde.
Although acetaldehyde is short lived, usually existing in the body only for a
brief time before it is further broken down into acetate, it has the potential
to cause significant damage. This is particularly evident in the liver, where
the bulk of alcohol metabolism takes place (4). Some alcohol metabolism also occurs
in other tissues, including the pancreas (3) and the brain, causing damage to
cells and tissues (1). Additionally, small amounts of alcohol are metabolized
to acetaldehyde in the gastrointestinal tract, exposing these tissues to acetaldehyde’s
damaging effects (5).

In addition to its toxic effects, some researchers
believe that acetaldehyde may be responsible for some of the behavioral and physiological
effects previously attributed to alcohol (6). For example, when acetaldehyde is
administered to lab animals, it leads to incoordination, memory impairment, and
sleepiness, effects often associated with alcohol (7).

On the other hand,
other researchers report that acetaldehyde concentrations in the brain are not
high enough to produce these effects (7). This is because the brain has a unique
barrier of cells (the blood–brain barrier) that help to protect it from
toxic products circulating in the bloodstream. It’s possible, however, that
acetaldehyde may be produced in the brain itself when alcohol is metabolized by
the enzymes catalase (8,9) and CYP2E1 (10).

THE GENETICS BEHIND METABOLISM

Regardless
of how much a person consumes, the body can only metabolize a certain amount of
alcohol every hour (2). That amount varies widely among individuals and depends
on a range of factors, including liver size (1) and body mass.

In addition,
research shows that different people carry different variations of the ADH and
ALDH enzymes. These different versions can be traced to variations in the same
gene. Some of these enzyme variants work more or less efficiently than others;
this means that some people can break down alcohol to acetaldehyde, or acetaldehyde
to acetate, more quickly than others. A fast ADH enzyme or a slow ALDH enzyme
can cause toxic acetaldehyde to build up in the body, creating dangerous and unpleasant
effects that also may affect an individual’s risk for various alcohol-related
problems—such as developing alcoholism.

The type of ADH and ALDH an
individual carries has been shown to influence how much he or she drinks, which
in turn influences his or her risk for developing alcoholism (11). For example,
high levels of acetaldehyde make drinking unpleasant, resulting in facial flushing,
nausea, and a rapid heart beat. This “flushing” response can occur
even when only moderate amounts of alcohol are consumed. Consequently, people
who carry gene varieties for fast ADH or slow ALDH, which delay the processing
of acetaldehyde in the body, may tend to drink less and are thus somewhat “protected”
from alcoholism (although, as discussed later, they may be at greater risk for
other health consequences when they do drink).

Genetic differences in these
enzymes may help to explain why some ethnic groups have higher or lower rates
of alcohol-related problems. For example, one version of the ADH enzyme, called
ADH1B*2, is common in people of Chinese, Japanese, and Korean descent
but rare in people of European and African descent (12). Another version of the
ADH enzyme, called ADH1B*3, occurs in 15 to 25 percent of African Americans
(13). These enzymes protect against alcoholism (14) by metabolizing alcohol to
acetaldehyde very efficiently, leading to elevated acetaldehyde levels that make
drinking unpleasant (15). On the other hand, a recent study by Spence and colleagues
(16) found that two variations of the ALDH enzyme, ALDH1A1*2 and ALDH1A1*3,
may be associated with alcoholism in African-American people.

Although these
genetic factors influence drinking patterns, environmental factors also are important
in the development of alcoholism and other alcohol-related health consequences.
For example, Higuchi and colleagues (17) found that as alcohol consumption in
Japan increased between 1979 and 1992, the percentage of Japanese alcoholics who
carried the protective ADH1B*2 gene version increased from 2.5 to 13 percent.
Additionally, despite the fact that more Native American people die of alcohol-related
causes than do any other ethnic group in the United States, research shows that
there is no difference in the rates of alcohol metabolism and enzyme patterns
between Native Americans and Whites (18). This suggests that rates of alcoholism
and alcohol-related problems are influenced by other environmental and/or genetic
factors.

HEALTH CONSEQUENCES OF ALCOHOL USE

Alcohol
metabolism and cancer—Alcohol consumption can contribute to
the risk for developing different cancers, including cancers of the upper respiratory
tract, liver, colon or rectum, and breast (19). This occurs in several ways, including
through the toxic effects of acetaldehyde (20).

Where Alcohol Metabolism Takes Place

Alcohol
is metabolized in the body mainly by the liver. The brain, pancreas, and stomach
also metabolize alcohol.

Many heavy drinkers do not develop
cancer, and some people who drink only moderately do develop alcohol-related cancers.
Research suggests that just as some genes may protect individuals against alcoholism,
genetics also may determine how vulnerable an individual is to alcohol’s
carcinogenic effects (5).

Ironically, the very genes that protect some people
from alcoholism may magnify their vulnerability to alcohol-related cancers. The
International Agency for Research on Cancer (21) asserts that acetaldehyde should
be classified as a carcinogen. Acetaldehyde promotes cancer in several ways—for
example, by interfering with the copying (i.e., replication) of DNA and by inhibiting
a process by which the body repairs damaged DNA (5). Studies have shown that people
who are exposed to large amounts of acetaldehyde are at greater risk for developing
certain cancers, such as cancers of the mouth and throat (5). Although these individuals
often are less likely to consume large amounts of alcohol, Seitz and colleagues
(5) suggest that when they do drink their risk for developing certain cancers
is higher than drinkers who are exposed to less acetaldehyde during alcohol metabolism.

Acetaldehyde
is not the only carcinogenic byproduct of alcohol metabolism. When alcohol is
metabolized by CYP2E1, highly reactive, oxygen-containing molecules—or reactive
oxygen species (ROS)—are produced. ROS can damage proteins and DNA or interact
with other substances to create carcinogenic compounds (22).

Fetal
Alcohol Spectrum Disorder (FASD)—Pregnant women who drink
heavily are at even greater risk for problems. Poor nutrition may cause the mother
to metabolize alcohol more slowly, exposing the fetus to high levels of alcohol
for longer periods of time (23). Increased exposure to alcohol also can prevent
the fetus from receiving necessary nutrition through the placenta (24). In rats,
maternal malnutrition has been shown to contribute to slow fetal growth, one of
the features of FASD, a spectrum of birth defects associated with drinking during
pregnancy (23). These findings suggest that managing nutrition in pregnant women
who drink may help to reduce the severity of FASD (25).

Alcoholic
liver disease—As the chief organ responsible for the breakdown
of alcohol, the liver is particularly vulnerable to alcohol metabolism’s
effects. More than 90 percent of people who drink heavily develop fatty liver,
a type of liver disease. Yet only 20 percent will go on to develop the more severe
alcoholic liver disease and liver cirrhosis (26).

Alcoholic
pancreatitis—Alcohol metabolism also occurs in the pancreas,
exposing this organ to high levels of toxic byproducts such as acetaldehyde and
FAEEs (3). Still, less than 10 percent of heavy alcohol users develop alcoholic
pancreatitis—a disease that irreversibly destroys the pancreas— suggesting
that alcohol consumption alone is not enough to cause the disease. Researchers
speculate that environmental factors such as smoking and the amount and pattern
of drinking and dietary habits, as well as genetic differences in the way alcohol
is metabolized, also contribute to the development of alcoholic pancreatitis,
although none of these factors has been definitively linked to the disease (27).

SIDEBAR

TRENDS IN RESEARCH

Investigators are studying
factors that influence alcohol metabolism, such as variations in the study subjects’
gender and ethnicity, genetic variations in alcohol-metabolizing enzymes, and
even the food subjects consumed that day. Two methods that are helping researchers
gain a better understanding of how alcohol is metabolized are the alcohol clamp
method, in which alcohol is given intravenously, and the use of specially grown
cells.

The alcohol clamp method. The speed at
which people absorb, distribute, and metabolize alcohol varies as much as three
or four times between individuals (1,2). The alcohol clamp is a method of administering
alcohol intravenously to subjects, allowing researchers to circumvent variations
in alcohol absorption. This technique enables researchers to administer precise
doses of alcohol to achieve an exact breath alcohol concentration (a measure of
how much alcohol is in the body) (3,4). The actual dose of alcohol is calculated
for each individual based on his or her specific alcohol elimination rate, controlling
for factors like gender and body mass. This allows researchers to compare the
alcohol elimination or metabolism rates without complicating factors. For example,
using the alcohol clamp method researchers were able to determine that male volunteers
eliminated alcohol at significantly faster rates than did female volunteers (5–8).
The alcohol clamp method also helps researchers study the genetics of alcohol
metabolism, including differences in how volunteers who carry different versions
of the ADH and ALDH genes metabolize alcohol (9).

Cultured cells.
Cells that are grown in the laboratory (i.e., cultured cells) are an important
tool in studying how alcohol damages the liver on a molecular level. Cultured
cells can help to clarify the processes associated with alcohol metabolism that
damage cells by allowing researchers to investigate individual metabolic pathways;
to control the cells’ exposure to alcohol and its byproducts; and to work
with uniform, or cloned, cells (10). Additionally, because large quantities of
cells can be cloned, researchers are able to repeat experiments many times in
order to confirm findings.

CONCLUSION

Researchers continue to
investigate the reasons why some people drink more than others and why some develop
serious health problems because of their drinking. Variations in the way the body
breaks down and eliminates alcohol may hold the key to explaining these differences.
New information will aid researchers in developing metabolism-based treatments
and give treatment professionals better tools for determining who is at risk for
developing alcohol-related problems.

Resources

Source
material for this Alcohol Alert originally appeared in a special two-part
series of Alcohol Research & Health that examines the topic of alcohol
metabolism.

Alcohol Research & Health, Vol. 29, No.
4, 2006: This issue describes alcohol’s metabolic pathways, their genetic
variation, and the effects of certain byproducts, such as acetaldehyde, on a range
of organs and tissues.

Alcohol Research & Health,
Vol. 30, No. 1, 2007. This issue examines how differences in metabolism may lead
to increased or reduced risk among individuals and ethnic groups for alcohol-related
problems such as alcohol dependence, cancer, fetal alcohol effects, and pancreatitis.

Full-text
articles from each issue of Alcohol Research & Health are available on
the NIAAA Web site at www.niaaa.nih.gov

Subscriptions
to Alcohol Research & Health are available from the Superintendent of
Documents for $25. Write to New Orders, Superintendent of Documents, P.O. Box
371954, Pittsburgh, PA 15250–7954; or fax 202-512-2250.

All material contained in the Alcohol Alert
is in the public domain and may be used or reproduced without permission from
NIAAA. Citation of the source is appreciated. Copies of the Alcohol Alert
are available free of charge from the National Institute on Alcohol Abuse
and Alcoholism Publications Distribution Center P.O. Box 10686, Rockville,
MD 20849–0686.